Epilepsy, one of the most common neurological conditions in the world, remains poorly controlled in about 675,000 Americans and costs $12.5 billion annually in the United States alone. Despite advances in drug and device therapy over several decades, we still have little understanding of how to tailor treatment based on known or suspected mechanisms of epileptogenesis in individual patients. Much evidence suggests that aberrant cortical connectivity plays a role in many forms of epilepsy, leading to changes in both local and network brain function. Noninvasive techniques such as transcranial magnetic stimulation (TMS) have the potential to not only probe but also modulate cortical hyperexcitability and functional connectivity in a safe and experimentally controlled manner. The identification of appropriate targets is critical for TMS, but difficult in patients who are nonlesional or have acquired epilepsy from heterogeneous insults. As a result, developmental malformations such as periventricular nodular heterotopia (PNH) have served as important model disorders for epileptogenesis because of their abnormal but readily characterized cerebral architecture. In this project we will use advanced brain imaging, physiological, and stimulation-based techniques in human subjects with PNH and matched controls, to accomplish three major goals: 1) We will map the abnormal circuitry in PNH that appears to connect misplaced gray matter nodules with the overlying cortex in this condition. Using diffusion tensor tractography and resting-state functional connectivity magnetic resonance imaging (fcMRI), we will identify discrete cortical partner regions for heterotopic nodules in PNH. 2) We will investigate cortical excitability within focal brain regions that show abnormal connectivity, by measuring electroencephalography (EEG) potentials induced by single- and paired-pulse TMS as a probe of excitation/inhibition (E/I) balance. We expect to demonstrate intrinsic hyperexcitability within regions of normal-appearing cortex that form aberrant circuits. 3) Finally, we will employ TMS in a continuous theta burst protocol, targeted at these identified cortical partner regions and matched control targets, to determine the neuromodulatory effects of stimulation in the epileptic brain. In particular, we will examine both network connectivity effects and local cortical effects of TMS using an experimental design that includes two functional biomarkers (fcMRI and cortical E/I balance) measured before and after each stimulation session. Patients with intractable seizures are a heterogeneous group with focal cortical lesions, aberrant neural circuitry, and other undetermined mechanisms of hyperexcitability. Ultimately, the ideal therapeutic approach will require clinicians to select treatment according to specifically identified epileptogenic mechanisms in individual patients, using interventions that have discretely measurable effects on these systems. Our work in brain imaging, cortical physiology, and noninvasive stimulation will make novel strides in this direction and will have a significant impact on clinical epilepsy care. PUBLIC HEALTH RELEVANCE: This project, which will investigate aberrant neural connectivity, cortical hyperexcitability, and the neuromodulatory effects of noninvasive magnetic stimulation in an epileptic brain malformation, will have significant implications for our understanding of how seizure disorders develop in the human brain and how best to treat them. The insights gained from this research will lead to additional, powerful tools for neurologists to employ when evaluating patients with uncontrolled seizures, and will directly shape the future usage of innovative therapeutic modalities in medically refractory epilepsy.